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Background the efficacy and safety of direct oral anticoagulants (DOACs) compared with that of warfarin in very old patients with non-valvular atrial fibrillation (NVAF) have been reported in terms of thromboembolisms and bleeding. However, the association of DOAC use and mortality in such patients remains unclear. Objectives this study aimed to investigate the incidence of mortality, as well as thromboembolisms and major bleeding, in very old patients with NVAF using DOACs as compared with warfarin. Methods we conducted a single-centre historical cohort study of consecutive patients with NVAF aged ≥80 years who used oral anticoagulants. We compared the 5-year outcomes (all-cause mortality, thromboembolism, major bleeding and intracranial haemorrhage) between the DOAC and Warfarin groups. Results of 1,676 patients with atrial fibrillation aged 80 years and over, 1,208 with NVAF were included. Propensity score matching provided 461 patients in each group, and the risk of all-cause mortality, thromboembolisms, major bleeding and intracranial haemorrhages was significantly lower in the DOAC group than Warfarin group (hazard ratio [95% confidence interval] for DOAC use, 0.68 [0.54–0.87], 0.31 [0.19–0.53], 0.56 [0.36–0.88], 0.23 [0.10–0.56], log-rank P = 0.002, P Conclusion patients with NVAF aged ≥80 years and using DOACs had a lower mortality than those using warfarin.

Aims The association between serum cholinesterase and prognosis in acute heart failure (AHF) remains to be elucidated. We investigated the serum cholinesterase level at discharge from hospitalization for AHF and its association with clinical outcomes in patients with AHF. Methods and results Among 4056 patients enrolled in the Kyoto Congestive Heart Failure multicentre registry, we analysed 2228 patients with available serum cholinesterase data. The study population was classified into three groups according to serum cholinesterase level at discharge: low tertile ( Conclusions Low serum cholinesterase levels are associated with congestive findings on echocardiography, higher BNP, and higher risks for a composite of all-cause death and HF hospitalization in patients with AHF.

AimThe impact of sex differences on the clinical outcomes of radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) is controversial. We investigated the sex differences regarding the efficacy and clinical outcomes of RFCA of AF.Methods and resultsWe conducted a large-scale, prospective, multicentre, observational study (Kansai Plus Atrial Fibrillation Registry). We enrolled 5010 consecutive patients who underwent an initial RFCA of AF at 26 centres (64 ± 10 years; non-paroxysmal AF, 35.7%). The median follow-up duration was 2.9 years. Female patients (n = 1369, 27.3%) were older (female vs. male, 68 ± 9 vs. 63 ± 11 years, P ConclusionsFemales experienced more frequent AF recurrences probably due to non-PV arrhythmogenicity and de novo pacemaker implantations than males during the long-term follow-up after RFCA of AF.

Background Since atrial functional tricuspid regurgitation (AF-TR) is associated with increased heart failure and mortality, the management of AF-TR is clinically important. Atrial fibrillation (AF) plays the main role in AF-TR. However, the effectiveness of catheter ablation (CA) and mechanism of improvement of AF-TR haven't been fully evaluated. Purpose We sought to investigate the impact of CA for AF on AF-TR in patients with moderate or more TR. Methods We retrospectively investigated consecutive 2685 patients with AF who received CA from February 2004 to December 2019 in Japan. The current study population consisted of 102 patients with moderate or greater TR who underwent CA for AF. The echocardiographic parameters were compared between pre-ablation and post-ablation transthoracic echocardiography (TTE), and the recurrence rate of AF/ atrial tachycardia (AT) was measured. Results The mean age was 73.2 years, 53% were women. TR severity and TR jet area significantly improved after CA for AF (TR jet area: 5.8 [3.9–7.6] cm2 to 2.0 [1.1–3.0] cm2, p Conclusions TR severity and jet area improved after CA in patients with AF and moderate or more TR. RV size, RA size, TV diameter also decreased after CA, which may be associated with TR improvement. There was no significant difference between one-year recurrence of AF/AT and TR severity at pre-ablation TTE. Funding Acknowledgement Type of funding sources: None.

Background/Introduction Patients with venous thromboembolism (VTE), including pulmonary embolism (PE), have a long-term risk of recurrence, and anticoagulation therapy is recommended for the prevention of recurrence. The latest 2019 European Society of Cardiology (ESC) guideline classified the risks of recurrence into low- (8%/year) risk, and recommended the extended anticoagulation therapy of indefinite duration for high-risk patients as well as intermediate-risk patients. However, extended anticoagulation therapy of indefinite duration for all of intermediate-risk patients have been a matter of active debate. Thus, additional risk assessment of recurrence in intermediate-risk patients might be clinically relevant in defining the optimal duration of anticoagulation therapy. Furthermore, bleeding risk during anticoagulation therapy should also be taken into consideration for optimal duration of anticoagulation therapy. However, there are limited data assessing the risk of recurrence as well as bleeding in patients with intermediate-risk for recurrence based on the classification in the latest 2019 ESC guideline. Purpose The current study aimed to identify the risk factors of recurrence as well as major bleeding in patients with intermediate-risk for recurrence, using a large observational database of VTE patients in Japan. Methods The COMMAND VTE Registry is a multicenter registry enrolling consecutive 3027 patients with acute symptomatic VTE among 29 centers in Japan. The current study population consisted of 1703 patients with intermediate-risk for recurrence. The primary outcome measure was recurrent VTE during the entire follow-up period, and the secondary outcome measures were recurrent VTE and major bleeding during anticoagulation therapy. Results In the multivariable Cox regression model for recurrent VTE incorporating the status of anticoagulation therapy as a time-updated covariate, off-anticoagulation therapy was strongly associated with an increased risk for recurrent VTE (HR 9.42, 95% CI 5.97–14.86). During anticoagulation therapy, the independent risk factor for recurrent VTE was thrombophilia (HR 3.58, 95% CI 1.56–7.50), while the independent risk factors for major bleeding were age ≥75 years (HR 2.04, 95% CI 1.36–3.07), men (HR 1.52, 95% CI 1.02–2.27), history of major bleeding (HR 3.48, 95% CI 1.82–6.14) and thrombocytopenia (HR 3.73, 95% CI 2.04–6.37). Conclusions Among VTE patients with intermediate-risk for recurrence, discontinuation of anticoagulation therapy was a very strong independent risk factor of recurrence during the entire follow-up period. The independent risk factors of recurrent VTE and those of major bleeding during anticoagulation therapy were different: thrombophilia for recurrent VTE, and advanced age, men, history of major bleeding, and thrombocytopenia for major bleeding. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Research Institute for Production Development, Mitsubishi Tanabe Pharma Corporation

Background/Introduction Cancer is a strong risk factor for the development of venous thromboembolism (VTE) including pulmonary embolism (PE) and deep vein thrombosis (DVT). Patients with VTE have a long-term risk of recurrence, which can be prevented by anticoagulation therapy. Prolonged anticoagulation therapy is recommended for patients with cancer-associated VTE, although the risk of recurrence might depend on the individual patient. Purpose We aimed to identify the risk factors of recurrence in patients with cancer-associated VTE. Methods The COMMAND VTE Registry is a multicenter retrospective registry enrolling 3027 consecutive patients with acute symptomatic VTE among 29 Japanese centers between January 2010 and August 2014. The present study population consisted of 695 cancer-associated VTE patients. The primary outcome measure in the present study was recurrent VTE, which was defined as PE and/or DVT with symptoms accompanied by confirmation of a new thrombus or exacerbation of the thrombus by objective imaging examinations or autopsy. Discontinuation of anticoagulation was defined as a withdrawal of anticoagulation therapy lasting >14 days for any reason. We selected clinically relevant variables and variables with P values Results Among the 695 study patients, recurrent VTE occurred in 78 patients, of whom 54 (69%) occurred within 6 months. The cumulative incidence of recurrent VTE was 7.7% at 3-months, 8.9% at 6-months, 11.8% at 1-year, and 17.7% at 5-years. The cumulative incidence of discontinuation of anticoagulation therapy was 18.0% at 3-months, 29.5% at 6-months, 43.4% at 1-year, and 66.5% at 5-years. The cumulative 5-year incidence of recurrent VTE was most frequent in patients with uterus/ovary cancer (26.0%), followed by those with lung cancer (24.7%). The multivariable Cox proportional hazard model revealed that chronic kidney disease (HR, 2.27; 95% CI, 1.36–3.77, P=0.002), a high D-dimer level at the time of VTE diagnosis (HR, 2.85; 95% CI, 1.71–4.74, P Conclusions Among patients with cancer-associated VTE, chronic kidney disease, a high D-dimer level at the time of VTE diagnosis, advanced cancer, and discontinuation of anticoagulation therapy were independent risk factors of recurrence. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Research Institute for Production Development, Mitsubishi Tanabe Pharma Corporation Figure 1Figure 2

Aims Early aortic valve replacement (AVR) might be beneficial in selected high-risk asymptomatic patients with severe aortic stenosis (AS), considering their poor prognosis when managed conservatively. This study aimed to develop and validate a clinical scoring system to predict AS-related events within 1 year after diagnosis in asymptomatic severe AS patients. Methods and results We analysed 1274 asymptomatic severe AS patients derived from a retrospective multicentre registry enrolling consecutive patients with severe AS in Japan (CURRENT AS registry), who were managed conservatively and completed 1-year follow-up without AVR. From a randomly assigned derivation set (N = 849), we developed CURRENT AS risk score for the AS-related event (a composite of AS-related death and heart failure hospitalization) within 1 year using a multivariable logistic regression model. The risk score comprised independent risk predictors including left ventricular ejection fraction Conclusion The CURRENT-AS risk score integrating clinical and echocardiographic factors well-predicted the risk of AS-related events at 1 year in asymptomatic patients with severe AS and was validated internally.

Background/Introduction Patients with cancer-associated venous thromboembolisms (VTEs) are at a high risk for recurrent VTEs and are recommended to receive prolonged anticoagulation therapy if they are at a low risk for bleeding. However, there are no established risk factors for bleeding during prolonged anticoagulation therapy. Purpose We aimed to identify the risk factors for major bleeding during prolonged anticoagulation therapy in cancer-associated VTE patients. Methods The COMMAND VTE Registry is a multicenter retrospective registry enrolling 3027 consecutive patients with acute symptomatic VTEs among 29 Japanese centers between January 2010 and August 2014. After excluding those without active cancer (N=2332), patients with major bleeding (N=15), death (N=17), and lost to follow-up (N=10) within 10 days after the diagnosis, and those without anticoagulation therapy beyond 10 days after the diagnosis (N=61), the present study population consisted of 592 cancer-associated VTE patients with anticoagulation therapy beyond 10 days after the diagnosis. The outcome measurement was International Society of Thrombosis and Hemostasis (ISTH) major bleeding during anticoagulation therapy beyond 10 days, which occurred before the first discontinuation of the anticoagulation therapy. We constructed a multivariable Cox proportional hazard model to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of the potential risk factors for major bleeding. As a sensitivity analysis, we used Fine and Gray's method to estimate the HR and 95% CI, taking into account the competing risk of all-cause death. Results During a median follow-up period of 199 days, major bleeding occurred in 72 patients (31 patients within 3 months; 41 beyond 3 months). The cumulative incidence of major bleeding was 5.8% at 3-months, 13.8% at 1-year, 17.5% at 2-year, and 28.1% at 5-years. The most frequent major bleeding site was gastrointestinal (47%), followed by intracranial (17%) and genitourinary (11%). Major bleeding tended to occur from the sites of the cancer, however, the sites of the cancer and sites of major bleeding were not necessarily concordant. The multivariable Cox regression model demonstrated that terminal cancer (adjusted HR, 4.17; 95% CI, 2.22–7.85, P Conclusions Major bleeding events were common during prolonged anticoagulation therapy in real-world cancer-associated VTE patients. Terminal cancer, chronic kidney disease, and gastrointestinal cancer were the independent risk factors for major bleeding. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Research Institute for Production Development, Mitsubishi Tanabe Pharma Corporation

Background Biodegradable polymer drug-eluting stents (BP-DES) has been developed to overcome the potential drawbacks of the first-generation durable polymer drug-eluting stents (DP-DES). However, it is still under debate whether BP-DES is associated with superior efficacy and safety over DP-DES. Purpose We sought to compare the effects of BP-DES and DP-DES in patients with coronary artery disease. Methods We performed systematic review and a meta-analysis of randomized controlled trials comparing BP-DES and DP-DES on clinical outcomes in patients with coronary artery disease using CE-mark approved drug-eluting stents (DES) with at least 1-year follow-up. We included 32 studies involving 39,686 patients (BP-DES: 21,439 patients, and DP-DES: 18,247 patients). Primary outcome measure was target vessel failure (TVF; equivalent to the composite of cardiac death, target-vessel myocardial infarction, or ischemia-driven target vessel revascularization). We performed subgroup analysis according to the DP-DES generations (newer-generation DP-DES: 15,179patients, and first-generation DP-DES: 3,068 patients), and the effects of newer-generation DP-DES was compared with the BP-DES according to the BP-DES strut thickness (Ultra-thin strut [ Results The odds for TVF was not significantly different between the BP-DES group and the DP-DES group in the entire study population (odds ratio [OR] 0.96, 95% confidence interval [CI] [0.90–1.02], P=0.20). The odds for TVF was significantly low in the BP-DES group relative to the first-generation DP-DES group, however the odds were comparable between the BP-DES group and the newer-generation DP-DES group (BP-DES versus first-generation DP-DES: OR 0.82, 95% CI [0.73–0.92], P Conclusions In this meta-analysis of randomized controlled trials evaluating clinical outcomes, there was no significant differences between BP-DES and DP-DES. We found beneficial effects of BP-DES relative to the first-generation DP-DES, however, there was no statistical differences between BP-DES and newer-generation DP-DES, irrespective of the BP-DES strut thickness. Pooled odds ratios for clinical outcomes Funding Acknowledgement Type of funding source: None

Background/Introduction Patients with cancer-associated venous thromboembolisms (VTEs) have a markedly higher risk of recurrence as well as bleeding, compared to those without, leading to difficulty in achieving a good risk-to-benefit balance with anticoagulation therapy. Thus, the assessment of the risk of recurrence in an individual patient is essential. The modified Ottawa score has been developed to predict the risk of recurrence in patients with cancer-associated VTEs during anticoagulation therapy, however, the validity of the score is still controversial. Purpose We aimed to evaluate the utility and limitations of the modified Ottawa score in the risk stratification of recurrent VTEs in patients with cancer-associated VTEs. Methods The COMMAND VTE Registry is a multicenter retrospective registry enrolling 3027 consecutive patients with acute symptomatic VTEs among 29 Japanese centers between January 2010 and August 2014. The present study population consisted of 614 cancer-associated VTE patients with anticoagulation therapy beyond 10 days after the diagnosis, who were divided into 3 groups; High-risk group with a modified Ottawa score ≥1, Intermediate-risk group with a score = 0, and Low-risk group with a score ≤−1. To evaluate the discriminating power of the modified Ottawa score for recurrence, we described the receiver operating characteristic curve with a C-statistic, and evaluated the positive likelihood ratio as the predictive performance of the score for recurrence in each subgroup. Results The high-risk group accounted for 202 patients (33%), intermediate-risk group for 269 (44%), and low-risk group for 143 (23%). During the first 6 months of anticoagulation therapy, recurrent VTEs occurred in 39 patients. The cumulative incidence of recurrent VTEs substantially increased in the higher risk categories by the modified Ottawa score (High-risk group: 13.6%, Intermediate-risk group: 5.9%, and Low-risk group: 3.0%, Log-rank P=0.02) (Figure 1). The discriminating power of the score was modest with a C-statistic of 0.63 (95% CI 0.55–0.71). The positive likelihood ratios as the predictive performance of the score were 1.71 in the high-risk group, 0.81 in the intermediate-risk group, and 0.42 in the low-risk group. Women and patients with prior VTEs had numerically higher cumulative 6-month incidences of recurrent VTEs compared with those without, while patients with lung cancer, breast cancer, and without metastasis had numerically lower cumulative 6-month incidences of recurrent VTEs. Depending on the presence or absence of each score component, the risks of recurrence seemed to differ in the low-, intermediate-, and high-risk groups. Conclusions The risks of recurrence in patients with cancer-associated VTEs substantially increased in the higher risk categories by using the modified Ottawa score, but the discriminating power of the score for recurrence was modest with a widely variable impact of each score component on recurrence. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Research Institute for Production Development, Mitsubishi Tanabe Pharma Corporation

Objective This study aimed to investigate the prognostic impact of the decrease in tricuspid regurgitation pressure gradient (TRPG) at 6-month follow-up in patients after discharge with heart failure (HF). Background No previous study has reported the association between TRPG decrease during follow-up and clinical outcomes in HF. Methods Among 748 patients with 6-months follow-up echocardiography after discharge from the acute decompensated heart failure in 19 centers in Japan, we analyzed 721 patients with available TRPG data and divided into two groups: the decrease in TRPG group (N=179) and no decrease in TRPG group (N=542). We defined the decrease in TRPG as >10mmHg decrease compared in the initial hospitalization. The primary outcome measure was a composite of all cause deaths and hospitalization due to HF. Results The patients in the decrease in TRPG group had a lower prevalence of hypertension, dyslipidemia, atrial fibrillation, and a reduced EF, higher levels of blood albumin and lower levels of sodium than those in no decrease in TRPG group. The median follow-up duration after the follow up echocardiography was 302 (inter quartile range: 206–490), with a 90.9% follow up rate at 6-month. The cumulative 6-month incidence of the primary outcome measure was significantly lower in the decrease in TRPG group than in no decrease in TRPG group (12.2% vs. 18.9%, P=0.0011). After adjusting confounders, the excess risk of the decrease in TRPG relative to no decrease in TRPG for the primary outcome measure remained significant (HR: 0.60, 95% CI 0.34–0.99). There were no significant interactions between the subgroup factors and the effect of the decrease in TRPG for primary outcomes. Conclusions HF patients with the decrease in TRPG at 6-month after discharge had a lower risk of clinical outcome than those without decrease in TRPG. Funding Acknowledgement Type of funding source: None

Background The predictors of arrhythmia recurrence after radiofrequency catheter ablation (RFCA) for paroxysmal atrial fibrillation (PAF) have not yet been fully evaluated. Purpose The aim of this study was to develop and validate a risk scoring system to predict the incidence of recurrence of atrial tachyarrhythmia after the final RFCA for PAF. Methods The study population consisted of 3223 consecutive patients undergoing first-time RFCA for PAF from November 2011 to March 2014 in 26 cardiovascular centers in Japan who were enrolled in the Kansai Plus Atrial Fibrillation (KPAF) registry. We developed a scoring system in a derivation cohort with 2149 patients and assessed its reproducibility in a validation cohort with 1074 patients. The primary endpoint was recurrent atrial tachyarrhythmia lasting for ≥30 seconds after 91 days post the final ablation. Results During a median follow-up period of 3.1 years, 404 (18.8%) patients of the derivation cohort had AF recurrence after the final RFCA. The baseline patient characteristics of the derivation cohort were as follows: mean age 64.7 years, male 1480 (68.9%), mean body mass index (BMI) 23.6 kg/m2, hypertension 1122 (52.2%), prior heart failure 182 (8.5%), diabetes mellitus 203 (9.5%), prior stroke and/or transient ischemic attack 21 (1.0%), prior vascular disease 209 (9.7%), prior valvular disease 105 (4.9%), median CHADS2 score 1.1, median CHA2DS2-VASc score 2.1, mean number of ineffective antiarrhythmic drugs (AAD) 0.80, median duration of history of AF episodes 2.1 years, mean left atrial diameter (LAD) 38.2 mm, mean left ventricular ejection fraction (LVEF) 65.3%, and mean eGFR 68.7 mL/min/1.73m2. There was no significant difference in the baseline characteristics between derivation and validation cohorts. The results of the multivariate logistic regression models identified 5 independent variables of recurrent atrial tachyarrhythmia after the final RFCA: female (odds ratio (OR) = 1.45, p=0.0017), BMI Conclusion Our newly developed scoring system, composed of female, BMI, AF duration, CKD, and LVEF, could reproducibly predict arrhythmia recurrence after the final RFCA for PAF. Funding Acknowledgement Type of funding source: None

Background The impact of sex differences on the clinical outcomes of radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) is controversial. We previously reported that females experienced more frequent AF recurrences than males after the index and last RFCA procedures. Purpose To identify the risk factors associated with recurrent AF in females and males after RFCA of AF. Methods We conducted a large-scale, prospective, multicenter, observational study (Kansai Plus Atrial Fibrillation Registry). We enrolled 5010 consecutive patients who underwent an initial RFCA of AF at 26 centers (64±10 years; 1369 [27.3%] females; non-paroxysmal AF, 35.7%). The median follow-up duration was 2.9 years. Results The incidence of AF recurrences after a single procedure was 43.3% in females and 39.0% in males. After a multivariate adjustment at baseline, the significant predictors of AF recurrence in females after the index RFCA were non-paroxysmal AF (hazard ration [HR],1.59; 95% confidence interval [CI],1.31–1.93, p Conclusion The Kansai Plus Atrial Fibrillation Registry revealed a distinct sex difference in terms of the predictors of recurrent AF after RFCA. Non-Paroxysmal AF and a long history of AF were common risk factors both in females and males. However, renal dysfunction was a significant predictor of AF recurrence in females, while it was not a risk of recurrence in males. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Research Institute for Production Development in Kyoto, Japan.

Background: The simplified pulmonary embolism severity index (sPESI) score has been reported to be useful in predicting 30-day mortality for patients with pulmonary embolism, which helps the identification of low-risk patients for early hospital discharge or home treatment. However, therapeutic decision-making should also be based on the risks of adverse events other than mortality. Methods: The COMMAND VTE Registry is a multicentre registry enrolling consecutive patients with acute symptomatic venous thromboembolism in Japan between January 2010 and August 2014, and the current study population consisted of 1715 patients with pulmonary embolism. We calculated the sPESI score for each patient, and compared 30-day rates of mortality, recurrent venous thromboembolism and major bleeding between sPESI scores of 0 and 1 or greater. Results: Patients with a sPESI score of 0 accounted for 383 (22%) patients, and 110 (6.4%) patients died within 30 days. The cumulative 30-day incidence of mortality was lower in patients with a sPESI score of 0 than those with a sPESI score of 1 or greater (0.5% vs. 8.1%, log rank PConclusions: In patients with a sPESI score of 0, the 30-day mortality, recurrent venous thromboembolism and major bleeding rates were reasonably low. The sPESI score could be useful to identify candidates for early hospital discharge or home treatment.

AIMS Tricuspid regurgitation (TR) has been reported to be associated with worse survival in various heart diseases, but there are few data in aortic stenosis (AS). METHODS AND RESULTS In the Contemporary Outcomes after Surgery and Medical Treatment in Patients with Severe Aortic Stenosis (CURRENT AS) Registry enrolling 3815 consecutive patients with severe AS, there were 628 patients with moderate or severe TR (TR group) and 3187 patients with no or mild TR (no TR group). The study patients were subdivided into the initial aortic valve replacement (AVR) stratum (n = 1197) and the conservative stratum (n = 2618) according to treatment strategy. The primary outcome measure was a composite of aortic valve-related death or hospitalization due to heart failure. The 5-year freedom rate from the primary outcome measure was significantly lower in the TR group than in the no TR group (49.1% vs. 67.3%, P

Background The relation between very low on-treatment low-density lipoprotein cholesterol (LDL-C) level and the cardiovascular event risk is still unclear in patients receiving the same doses of statins. Methods From the REAL-CAD study comparing high-dose with low-dose pitavastatin therapy in Japanese patients with stable coronary artery disease, 11105 patients without reported non-adherence for the study drug were divided into 3 groups according to the on-treatment LDL-C level at 6-month ( Results In the pitavastatin 1 mg/day stratum, cumulative 4-year incidence of the primary outcome measure was not significantly different across the 3 groups (5.0%, 5.7%, and 5.2%, P=0.51), while in the 4 mg/day stratum, it was significantly higher in the LDL-C ≥100 mg/dL group than in other groups (4.5%, 3.4%, and 9.1%, P Adjusted Effects of On-treatment LDL-C Conclusions Very low on-treatment LDL-C level ( Acknowledgement/Funding The Comprehensive Support Project for Clinical Research of Lifestyle-Related Disease of the Public Health Research Foundation.

Background/Introduction There is still uncertainty about the optimal usage of thrombolysis for acute pulmonary embolisms (PEs), leading to widely varying usage of thrombolysis in the real world. However, these have not been fully evaluated yet. Purpose We sought to evaluate the management strategies and clinical outcomes of thrombolysis for acute PEs in the real world. Methods The COMMAND VTE Registry is a multicenter registry enrolling 3,027 consecutive patients with acute symptomatic venous thromboembolisms in Japan between January 2010 and August 2014. The present study population consisted of 1,549 patients with PEs who received tissue plasminogen activator (t-PA) thrombolysis (N=180, 12%), or those who did not (N=1,369). The effectiveness outcome was all-cause death. The safety outcome was major bleeding. We used a multivariable logistic regression analysis to estimate the odds ratio (OR) and 95% confidence intervals (CI), to adjust clinically relevant confounders (age, sex, history of major bleeding, active cancer, and anemia). Additionally, we conducted stratified analysis by clinical severity, and we also evaluated clinical outcomes according to dosages of t-PA. Results Patients with t-PA thrombolysis were younger, and more frequently had higher body weight, but less frequently had active cancer, history of major bleeding, and anemia. More than half of patients with t-PA thrombolysis were patients with mild PEs, and the proportions of t-PA thrombolysis varied widely across the participating centers. More than half of patients received low-dose of t-PA ( Conclusions In the present real-world registry, relatively large number of patients received t-PA thrombolysis with wide variation across the participating centers. T-PA thrombolysis was significantly associated with a higher risk for major bleeding, but not a lower risk for mortality, although there appeared to be a benefit of t-PA thrombolysis in decreasing the risk for mortality in patients with severe PEs. Acknowledgement/Funding Research Institute for Production Development, Mitsubishi Tanabe Pharma Corporation

Background Heart failure (HF) is the leading cause of death in patients with atrial fibrillation (AF). Radiofrequency catheter ablation (RFCA) for AF is effective to maintain sinus rhythm. Purpose We sought to clarify whether AF ablation outcome influenced incidence of HF hospitalization after the procedures. Methods We conducted a large-scale, prospective, multicenter, observational study. A total of 5010 consecutive patients who underwent an initial RFCA for AF in 26 centers were enrolled (average age, 64±10 years; non-paroxysmal AF, 35.6%). The median follow-up duration was 2.9 years. Results The 3-year cumulative incidence of AF recurrence after a single procedure was 40.2%. The 3-year incidence of hospitalization for HF was observed in 92 patients (1.8%) and was significantly higher in patients with AF recurrence than those without it (3.3% vs 0.84%, log-rank p Conclusions Among AF patients receiving RFCA, those with AF recurrence were at greater risk of heart failure hospitalization than were patients without AF recurrence. These differences should be noted when treating AF patients in actual clinical practice. Acknowledgement/Funding This study was supported by the Research Institute for Production Development in Kyoto, Japan.

Background Heart failure (HF) is the leading cause of death in patients with atrial fibrillation (AF), and AF is an independent prognostic factor in HF patients with preserved left ventricular ejection fraction (LVEF). Radiofrequency catheter ablation (RFCA) for AF is effective to maintain sinus rhythm. Purpose We sought to clarify incidence of HF hospitalization and whether AF ablation outcome influenced incidence of HF hospitalization after the procedures in patients with preserved LVEF. Methods We conducted a large-scale, prospective, multicenter, observational study. A total of 4522 consecutive patients with normal LVEF (>/- 50%) who underwent an initial RFCA for AF in 26 centers were enrolled (average age, 64±10 years; non-paroxysmal AF, 33.7%). The median follow-up duration was 2.9 years. Results The 3-year cumulative incidence of AF recurrence after a single procedure was 40.3%. Hospitalization for HF was observed in 60 patients (1.3%) and was significantly higher in patients with AF recurrence than those without it (2.63% vs 0.44%, log-rank p Conclusions Recurrence after RFCA for AF was a significant risk of HF hospitalization among AF patients with preserved LVEF. Acknowledgement/Funding This study was supported by the Research Institute for Production Development in Kyoto, Japan.

Background The favourable effect of mineralocorticoid receptor antagonists (MRAs) on mortality was established in patients with stable heart failure (HF) with reduced ejection fraction (EF). However, its prognostic effect of MRAs in acute decompensated heart failure (ADHF) including HF with preserved EF (HFpEF) was unclear. Purpose This study sought to investigate the long-term impact of MRA on the post-discharge outcomes in patients with ADHF. Methods From the consecutive 3717 patients hospitalized for ADHF and discharged alive in the KCHF registry, we developed the propensity score (PS) for MRA use and constructed the PS-matched cohort. We compared the effect of MRA use on the primary outcome measure of all-cause death or HF hospitalization. Results A total of 1678 patients (45%) received MRA at discharge from the index hospitalization. Median follow-up was 470 days with 96% 1-year follow-up rate. In the PS-matched cohort (N=1034 in each group), the cumulative 1-year incidence of the primary outcome measure was significantly lower in the MRA group than in the no MRA group (28.4% vs. 33.9%, P=0.003) (Figure 1). The cumulative 1-year incidence of HF hospitalization was significantly lower in the MRA group than in the no MRA group (18.7% vs. 24.8%, P Figure 1 Conclusion The use of MRA was associated with lower risk for the primary composite outcome of all-cause death or HF hospitalization in patients hospitalized for ADHF including HFpEF, which was mainly driven by the lower risk for HF hospitalization.

Background The current guidelines recommend different medical treatment strategies for heart failure (HF) patients according to category of left ventricular ejection fraction (LVEF). Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACE-I/ARB) is an established medical treatment for heart failure with reduced ejection fraction (HFrEF), whereas its usefulness remains to be elucidated for non-HFrEF, especially for heart failure with mid-range ejection fraction (HFmrEF). Purpose This study aimed to assess the difference in association between ACE-I/ARB and clinical outcomes depending on LVEF category. Methods The Kyoto Congestive Heart Failure (KCHF) Registry is a multicentre registry without any exclusion criteria which included consecutive patients hospitalized for congestive HF in Japan. In each LVEF group (HFrEF, HFmrEF and heart failure with preserved ejection fraction [HFpEF]), we compared those who were prescribed ACE-I/ARB as discharge medication and those not, and assessed their 1-year clinical outcomes. We defined the primary outcome measure as a composite of all-cause death and HF hospitalization. We constructed a multivariable Cox regression model incorporating 24 clinically relevant factors. We assessed adjusted hazard ratios (HRs) of those with ACE-I/ARB relative to those not, and also interaction between ACE-I/ARB prescription at discharge and LVEF category. Results A total of 3717 patients were included in this study, where the number of patients in each LVEF group were as follows; 1383 patients with HFrEF, 703 with HFmrEF and 1631 with HFpEF, respectively (Figure). As shown in the table, the HRs for the primary outcome measure were significant in the HFrEF and HFmrEF groups, whereas the HR in the HFpEF group was insignificant. The interaction between ACE-I/ARB prescription and LVEF category for the primary outcome measure was statistically significant. Hazard ratios by LVEF category Outcome measures HFrEF HFmrEF HFpEF P interaction HR (95% CI) P value HR (95% CI) P value HR (95% CI) P value All-cause death + HF hospitalization 0.66 (0.54–0.79) Study flowchart Conclusions The risk ratios of those who were prescribed ACE-I/ARB relative to those not were significantly low in HFmrEF as well as HFrEF, whereas the risk ratios were insignificant in HFpEF. ACE-I/ARB could be a potential choice of treatment for HFmrEF patients.

Background/Introduction Pulmonary embolism (PE) is caused by blockage of pulmonary arteries by thrombus. The sources of thrombus are thought to be mostly veins in lower extremities, whereas deep vein thrombosis (DVT) in upper extremities rarely occurs spontaneously. Recent studies reported that DVT in upper extremities might have significant complications, and DVT in upper extremities could be increasing. However, there is a paucity of data on patients with DVT in upper extremities, leading to uncertainty in optimal treatment strategies including anticoagulation therapy. Purpose We sought to evaluate the clinical characteristics, management strategies, and long-term outcomes of patients with DVT in upper extremities in a large observational database in Japan. Methods The COMMAND VTE Registry is a multicenter registry enrolling 3027 consecutive patients with acute symptomatic venous thromboembolism (VTE) objectively confirmed by imaging examination or by autopsy among 29 centers in Japan between January 2010 and August 2014. The current study population consisted of 2498 patients with DVT in upper or lower extremities, after excluding 381 patients with PE only, 144 patients who had thrombus in locations other than upper or lower extremities, and 4 patients with DVT in both upper and lower extremities. The study patients were divided into 2 groups: patients with DVT in upper extremities and patients with DVT in lower extremities. We compared the clinical characteristics, management strategies and long-term outcomes between the 2 groups. Results There were 74 patients (3.0%) with upper extremities DVT and 2498 patients (97%) with lower extremities DVT. Patients with upper extremities DVT more often had active cancer at diagnosis (58%) and central venous catheter use (22%). The proportion of concomitant PE at diagnosis was lower in patients with upper extremities DVT than in those with lower extremities DVT (14% and 51%, P Kaplan-Meier event curves for recurrence Conclusions The prevalence of patients with DVT in upper extremities was 3.0% in the current large-scale real-world registry. Patients with DVT in upper extremities more often had active cancer at diagnosis and central venous catheter use as a transient risk factor for VTE, and less often had concomitant PE. Patients with DVT in upper extremities had similar long-term risk for recurrent VTE as those with DVT in lower extremities despite shorter duration of anticoagulation. Acknowledgement/Funding Research Institute for Production Development, Mitsubishi Tanabe Pharma Corporation

Background Statin prevents occurrence and recurrence of atherosclerotic events. With regard to venous thromboembolism (VTE), a randomized controlled trial suggested that statin reduced occurrence of VTE, whereas its usefulness as secondary prevention of VTE remains to be elucidated. Purpose This study aimed to assess the association between statin prescription, recurrent VTE and bleeding events in patients with VTE. Methods The COMMAND VTE Registry is a multicentre registry enrolling consecutive 3027 patients with acute symptomatic VTE among 29 centres in Japan. We divided the cohort into the patients who were prescribed statin (N=437) and those not (N=2590), and compared the two groups. We assessed hazard ratios (HRs) of those with statin relative to those without for long-term clinical outcomes (recurrent symptomatic VTE and International Society of Thrombosis and Hemostasis [ISTH] major bleeding). Because the durations of anticoagulation therapy were widely different between the two groups, we constructed Cox's proportional hazard model incorporating status of anticoagulation during the follow-up period as a time-varying covariate. Also, because the incidences of death were strikingly different between the two groups due to the difference in the prevalence of active cancer, we used Fine-Gray's subdistribution hazard model in the presence of competing risks. We incorporated clinically relevant factors into these two models as covariates (10 factors for recurrent VTE and 11 for major bleeding). Results The statin group was significantly older than the non-statin group (statin 71.2±11.8 vs. non-statin 66.5±15.8, P Adjusted hazard ratios Outcome measures Model 1 P value Model 2 P value Adjusted HR [95% CI] Adjusted HR [95% CI] Recurrent VTE 0.59 [0.36–0.98] 0.042 0.53 [0.32–0.89] 0.02 Major bleeding 0.87 [0.60–1.24] 0.43 0.997 [0.69–1.43] 0.99 Model 1 derived from Cox's model with time-varying covariate of anticoagulation status. Model 2 derived from Fine-Gray's model. Study flowchart Conclusions Prescription of satin was associated with significantly low risks for recurrent VTE, whereas that was not for major bleeding events. Statin could be a potential treatment option for secondary prevention of VTE.

Background Impact of hyponatremia improvement on prognosis in patients with acute decompensated heart failure (ADHF) remains unclear. Methods Patients hospitalized for ADHF at 19 hospitals in Japan were enrolled between October 2014 and March 2016. Hyponatremia was defined as serum sodium concentration less than 135 mmol/l. Primary endpoint was composite of all-cause death and heart failure rehospitalization one year after discharge. Results Among 3805 patients enrolled, 486 patients with hyponatremia at admission showed higher in-hospital mortality (13.3% vs. 5.4%, p Patient characteristics Group P (n=143) Group I (n=253) p value Age (years) 81 (72–86) 81 (72–87) 0.73 Female 71 (49.7) 110 (43.5) 0.24 Ischemic etiology 42 (29.4) 81 (32.0) 0.58 Prior hospitalization 62 (43.7) 98 (39.5) 0.42 SBP at admission (mmHg) 140±36 144±38 0.40 HR at admission (bpm) 92±23 95±29 0.27 Atrial Fibrillation 47 (32.9) 103 (40.7) 0.12 NYHA class IV 60 (42.2) 138 (54.8) 0.02 Intravenous inotropic use 35 (24.5) 59 (23.3) 0.80 LVEF Conclusion Improvement of hyponatremia at discharge was not associated with better prognosis in patients hospitalized for ADHF.

Background Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), has significant morbidity and mortality. Acute PE, in particular, is fatal if we miss it, and symptomatic patients of PE sometimes have concomitant DVT. Purpose This study compared the risk of mortality in symptomatic patients of PE with and those without DVT in the long term. Methods The COMMAND VTE Registry is a multicenter registry enrolling consecutive 3027 patients with acute symptomatic VTE objectively confirmed by imaging examination or by autopsy among 29 centers in Japan between January 2010 and August 2014. Patients with both PE and DVT (N=1334) were regarded as PE patients, and the current study population consisted of 1715 PE patients and 1312 DVT patients. Results There were 1203 symptomatic patients of PE, including 381 without and 822 with DVT. In our cohort, the mean age was 67.9±14.9 years, 63% was female, 44% had hypertension, 12% diabetes mellitus, 5% history of VTE. There were 20% of active cancer. Baseline characteristics were well matched except for dyslipidemia (18% vs. 23%, p=0.021) and atrial fibrillation (8% vs. 5%, p=0.045). Patients without DVT had a more severe clinical presentation compared to those with DVT, including hypoxemia, shock and arrest. Moreover, Initial parenteral anticoagulation therapy in the acute phase was administered less frequently in patients without DVT (89% vs. 96%, P=0.0001). Two groups received thrombolysis (20% vs. 26%, P=0.18) and mechanical supports (Ventilator 14% vs. 5%, p Landmark analysis Conclusions In symptomatic patients of PE, there was a difference in mortality between groups, but no difference in recurrent VTE. Patients without DVT had a more severe clinical presentation compared to those with DVT, and many VTE-related deaths in the acute phase. The one-month mortality rate differed statistically between groups, but there was no significant difference in long-term survival beyond one month. Most of deaths were due to underlying diseases, mainly cancer, and less commonly due to VTE in the long term. Acknowledgement/Funding Research Institute for Production Development, Mitsubishi Tanabe Pharma Corporation

Background/Introduction Venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT), has a long-term risk for recurrence, which can be prevented by anticoagulation therapy. The duration of anticoagulation therapy after VTE should be based on the balance between risks of recurrent VTE and bleeding. However, there is uncertainty about the impact of these events on subsequent mortality. Purpose We sought to evaluate the impact of recurrent VTE events and bleeding events on subsequent mortality in patients with VTE in a large retrospective observational database in Japan. Methods We evaluated the association of recurrent VTE and major bleeding with mortality among 3026 patients in the COMMAND VTE Registry. We estimated the risks of recurrent VTE events and major bleeding events for subsequent all-cause death with the multivariable Cox proportional hazard model. We incorporated the recurrent VTE events and major bleeding events during follow-up into the multivariable Cox model as time-updated covariates together with the clinically-relevant 16 risk-adjusting factors. We expressed the adjusted risks of each covariate as hazard ratios (HR) and their 95%confidence intervals (CI). Furthermore, to assess the risks of recurrent PE and recurrent DVT events for subsequent all-cause death respectively, we divided recurrent VTE events into recurrent PE (PE with or without DVT) and recurrent DVT (DVT only), and incorporated these events as well as major bleeding events into the multivariable Cox model as time-updated covariates. Results In the current study population, the mean age was 67 years, 61% were women, and mean body weight and body mass index were 57.9 kg and 23.2 kg/m2, respectively. During the median follow-up period of 1,218 days, 763 patients died, 225 patients developed recurrent VTE events, and 274 patients developed major bleeding events. The time-updated multivariable Cox proportional hazard model revealed that both the recurrent VTE events and the major bleeding events were strongly associated with subsequent mortality risk (recurrent VTE events: HR 3.24, 95% CI 2.57–4.08, P Conclusions In the real-world patients with VTE, both recurrent VTE events and major bleeding events were strongly associated with subsequent mortality risk with the comparable effect size. Recurrent PE and recurrent DVT events were also associated with increased risks for mortality, although the magnitude of the effect on mortality was numerically greater with the recurrent PE events than with the recurrent DVT events. Acknowledgement/Funding Research Institute for Production Development, Mitsubishi Tanabe Pharma Corporation

Aims To evaluate the influence of a history of cancer on clinical outcomes in coronary artery disease (CAD) patients who underwent percutaneous coronary intervention (PCI). Methods and results In the Coronary REvascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) PCI/coronary artery bypass grafting (CABG) Registry Cohort-2, there were 12 180 CAD patients who received PCI with stents. There were 1109 patients with a history of cancer (cancer group) and 11 071 patients without cancer (non-cancer group). The cumulative 5-year incidences of cardiac death and heart failure (HF) hospitalization were significantly higher in the cancer group than in the non-cancer group (12.4% vs. 7.5%, P

[Aim]To investigate the effect of malignancy on the outcomes of patients with severe aortic stenosis (AS) and the management strategy for AS with malignancy. [Methods and results]Using data of 3815 patients with severe AS in a retrospective multicentre registry [CURRENT AS (Contemporary outcomes after sURgery and medical tREatmeNT in patients with severe Aortic Stenosis) registry], we compared 3-year clinical outcomes among three groups based on malignancy status: with malignancy currently under treatment including best supportive care (malignancy group), with a history of malignancy without any current treatment (past history group), or without history of malignancy (no malignancy group). Patients in the malignancy group (n = 124) were more often men and had higher prevalence of low body mass index, recurrence of malignancy, anaemia, and asymptomatic status, despite comparable surgical risks and echocardiographic parameters. The malignancy group or the past history group (n = 389) had significantly higher risk for all-cause death [hazard ratio (HR) 2.49, 95% CI (95% confidence interval) 1.98–3.14; HR 1.23, 95% CI 1.04–1.46] and for malignancy-related death (HR 16.2, 95% CI 10.64–24.54; HR 3.66, 95% CI 2.43–5.52) than that of the no malignancy group (n = 3302). The excess risk for aortic valve-related death was not observed in the malignancy group (HR 0.79, 95% CI 0.48–1.29) and was lower in the past history group (HR 0.72, 95% CI 0.53–0.96). In the malignancy group, the treatment strategy (surgery: n = 16, conservative management: n = 108) was determined based on the clinical status of AS or life expectancy. [Conclusions]Malignancy had marked effect on all-cause death and malignancy-related death in patients with severe AS. History of malignancy also had a smaller but significant effect on mortality.

BACKGROUND Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in the homeostasis of mucosal immunity; however, their role in inflammatory bowel disease (IBD) is unclear. METHODS Flow cytometry was used to enumerate peripheral blood MAIT cells in 88 patients with ulcerative colitis (UC), 68 with Crohn's disease (CD), and in 57 healthy controls. Immunohistochemistry identified MAIT cells in intestinal tissue samples from patients with UC (n = 5) and CD (n = 10), and in control colon (n = 5) and small intestine (n = 9) samples. In addition, expression of activated caspases by MAIT cells in the peripheral blood of 14 patients with UC and 15 patients with CD, and 16 healthy controls was examined. RESULTS Peripheral blood analysis revealed that patients with IBD had significantly fewer MAIT cells than healthy controls (P < 0.0001). The number of MAIT cells in the inflamed intestinal mucosae of patients with UC and CD was also lower than that in control mucosae (P = 0.0079 and 0.041, respectively). The number of activated caspase-expressing MAIT cells in the peripheral blood of patients with UC and CD was higher than that in healthy controls (P = 0.0061 and 0.0075, respectively), suggesting that the reduced MAIT cell numbers in IBD are associated with an increased level of apoptosis among these cells. CONCLUSIONS The number of MAIT cells in the peripheral blood and inflamed mucosae of patients with UC and CD was lower than that in non-IBD controls. Also, MAIT cells from patients with IBD exhibited proapoptotic features. These data suggest the pathological involvement and the potential for therapeutic manipulation of these cells in patients with IBD.

Male germ cells undergo dynamic epigenetic reprogramming during fetal development, eventually establishing spermatogonial stem cells (SSCs) that can convert into pluripotent stem cells. However, little is known about the developmental potential of fetal germ cells and how they mature into SSCs. We developed a culture system for fetal germ cells that proliferate for long periods of time. Male germ cells from embryos 12.5–18.5 days postcoitum could expand by glial cell line-derived neurotrophic factor, a self-renewal factor for SSCs. These cells did not form teratomas, but repopulated seminiferous tubules and produced spermatogenesis, exhibiting spermatogonia potential. However, the offspring from cultured cells showed growth abnormalities and were defective in genomic imprinting. The imprinting defect persisted in both the male and female germlines for at least four generations. Moreover, germ cells in the offspring showed abnormal histone modifications and DNA methylation patterns. These results indicate that fetal germ cells have a limited ability to become pluripotent cells and lose the ability to undergo epigenetic reprogramming by in vitro culture.

Spermatogenesis originates from a small number of spermatogonial stem cells that can reinitiate spermatogenesis and produce germ cell colonies following transplantation into infertile recipient testes. Although several previous studies have suggested a single-cell origin of germ cell colonies, only indirect evidence has been presented. In this investigation, we tested the clonal origin hypothesis using a retrovirus, which could specifically mark an individual spermatogonial stem cell. Spermatogonial stem cells were infected in vitro with an enhanced green fluorescence protein-expressing retrovirus and subsequently transplanted into infertile recipient mice. Live haploid germ cells were recovered from individual colonies and were microinjected into eggs to create offspring. In total, 45 offspring were produced from five colonies, and 23 (51%) of the offspring were transgenic. Southern blot analysis indicated that the transgenic offspring from the single colony carried a common integration site, and the integration site was different among the transgenic offspring from different colonies. These results provide evidence that germ cell colonies develop from single spermatogonial stem cells.

Spermatogenesis originates in spermatogonial stem cells, which have the unique mode of replication. It is considered that a single stem cell can produce two stem cells (self-renewing division), one stem and one differentiating (asymmetric division), or two differentiating cells (differentiating division). However, little is known regarding how each type of division is regulated. In this investigation, we focused on the analysis of self- renewing division and examined the effect of the pituitary gland using two models of stem cell self-renewing division. In the first experiment using newborn mice, the administration of GnRH- analogue, which represses the release of gonadotropin, reduced the number of stem cells during postnatal testicular development, suggesting that the pituitary gland enhances stem cell self- renewing division. In the second experiment, however, the number of stem cells increased dramatically in hypophysectomized adult recipients after spermatogonial transplantation. Thus, the p...

Spermatogenesis is dependent on a small population of stem cells. Although stem cells are believed to expand infinitely, there is little functional evidence regarding whether spermatogonial stem cells can increase in their number. Using the spermatogonial transplantation technique, we evaluated the proliferative potential of spermatogonial stem cells in two models of regeneration. After busulfan injection to deplete stem cells, the surviving stem cells were able to expand by at least 15.8-fold within 2 mo. On the other hand, a serial transplantation study indicated that one transplanted stem cell was able to expand by 3.8- and 12-fold within 2 and 4 mo, respectively. These results provide direct functional evidence for the expansion of stem cells and establish the basis for further characterization of the stem cell self-renewal process.